Serotonin is a neurotransmitter that modulates a wide range of behaviors and physiological processes, including feeding, movement, reproduction, respiration, sleep and affect. Serotonergic neurons are unique in terms of their development, morphological plasticity and function. They elaborate complex axon arbors over specific target regions. The importance of this development is reflected in the numerous psychiatric and cognitive disorders that have their roots in the improper development of serotonergic circuits. The serotonin neurotransmitter is also able to feed back onto serotonergic neurons to plastically reshape the axon arbors and presynaptic release sites. The molecular mechanisms that regulate the development and plasticity of serotonergic axon arbors and synapses are not yet understood, and are the purpose of this proposal. Serotonergic pathways are well conserved throughout evolution. We recently developed a system that allows us to assay serotonergic neuron morphogenesis and synaptogenesis in vivo, in real time and with single cell resolution in C. elegans. We plan to use this system to answer the following questions: 1) What are the cellular and molecular mechanisms that spatially restrict serotonergic axon arborization? 2) What are the molecular mechanisms the control serotonergic synapse assembly? and 3) What are the molecular mechanisms that control sertotonergic synapse plasticity? In summary, the approaches proposed here will allow us to dissect the molecular mechanisms that regulate serotonergic synapse development and plasticity. Given the conserved nature of serotonergic circuits, we expect the mechanisms uncovered in these studies to inform how serotonergic circuits are physiologically regulated in development and disease. PUBLIC HEALTH RELEVANCE: Project Narrative: Serotonin is a conserved neurotransmitter that modulates behaviors and physiological processes such as feeding, movement, reproduction, respiration, sleep and affect. The importance of this neuromodulator in the proper functioning of the nervous system is perhaps best exemplified by the multiplicity of human psychiatric disorders that have their roots in serotonergic dysfunction. In spite of the importance of serotonergic circuit neurodevelopment in physiology and disease, the mechanisms that control this process remain largely unknown. Here we propose to use the nematode C. elegans to dissect the cellular and molecular mechanisms that regulate serotonergic synapse development and plasticity. Given the conserved nature of serotonergic circuits, we expect the mechanisms uncovered in these studies to inform how serotonergic circuits are physiologically regulated in development and disease.